A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration

Adam C O'Neill; Christina Kyrousi; Johannes Klaus; Richard J Leventer; Edwin P Kirk; Andrew Fry; Daniela T Pilz; Tim Morgan; Zandra A Jenkins; Micha Drukker; Samuel F Berkovic; Ingrid E Scheffer; Renzo Guerrini; David M Markie; Magdalena Götz; Silvia Cappello; Stephen P Robertson

doi:10.1016/j.celrep.2018.11.029

A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration

Cell Rep. 2018 Dec 4;25(10):2729-2741.e6. doi: 10.1016/j.celrep.2018.11.029.

Authors

Adam C O'Neill¹, Christina Kyrousi², Johannes Klaus², Richard J Leventer³, Edwin P Kirk⁴, Andrew Fry⁵, Daniela T Pilz⁶, Tim Morgan⁷, Zandra A Jenkins⁷, Micha Drukker⁸, Samuel F Berkovic⁹, Ingrid E Scheffer¹⁰, Renzo Guerrini¹¹, David M Markie¹², Magdalena Götz¹³, Silvia Cappello¹⁴, Stephen P Robertson¹⁵

Affiliations

¹ Department of Women's and Children's Health, University of Otago, Dunedin, New Zealand; Institute of Stem Cell Research, Helmholtz Center, Munich, Germany; Physiological Genomics, Biomedical Center Ludwig-Maximilians-Universitaet, Munich, Germany.
² Max Planck Institute of Psychiatry, Munich, Germany.
³ Department of Neurology, Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia.
⁴ Sydney Children's Hospital, University of New South Wales, Randwick, NSW, Australia; New South Wales Health Pathology, Randwick, NSW, Australia.
⁵ Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK.
⁶ West of Scotland Genetics Service, Laboratory Medicine Building, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
⁷ Department of Women's and Children's Health, University of Otago, Dunedin, New Zealand.
⁸ Institute of Stem Cell Research, Helmholtz Center, Munich, Germany.
⁹ Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
¹⁰ Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia.
¹¹ Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
¹² Department of Pathology, University of Otago, Dunedin, New Zealand.
¹³ Institute of Stem Cell Research, Helmholtz Center, Munich, Germany; Physiological Genomics, Biomedical Center Ludwig-Maximilians-Universitaet, Munich, Germany; Excellence Cluster of Systems Neurology (SYNERGY), 82152 Planegg/Martinsried, Germany.
¹⁴ Max Planck Institute of Psychiatry, Munich, Germany. Electronic address: silvia_cappello@psych.mpg.de.
¹⁵ Department of Women's and Children's Health, University of Otago, Dunedin, New Zealand. Electronic address: stephen.robertson@otago.ac.nz.

PMID: 30517861
DOI: 10.1016/j.celrep.2018.11.029

Abstract

The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with the structural brain malformation periventricular nodular heterotopia (PH). De novo coding variants were observed in excess in genes defining a transcriptomic signature of basal radial glia, a cell type linked to brain evolution. In addition, we located two variants in human isoforms of two genes that have no ortholog in mice. Modulating the levels of one of these isoforms for the gene PLEKHG6 demonstrated its role in regulating neuroprogenitor differentiation and neuronal migration via RhoA, with phenotypic recapitulation of PH in human cerebral organoids. This suggests that this PLEKHG6 isoform is an example of a primate-specific genomic element supporting brain development.

Keywords: MyoGEF; PLEKHG6; RhoA; cortical development; evolution; periventricular heterotopia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Animals
Base Sequence
Brain / embryology
Brain / metabolism
Cell Movement*
Exome / genetics
Gene Expression Regulation
Genome
Guanine Nucleotide Exchange Factors / genetics
Guanine Nucleotide Exchange Factors / metabolism*
HEK293 Cells
Humans
Infant, Newborn
Male
Mice, Inbred C57BL
Neural Stem Cells / metabolism
Neurogenesis*
Neuroglia / metabolism
Neurons / cytology*
Neurons / metabolism*
Organoids / embryology
Primates
Protein Isoforms / metabolism
Species Specificity
rhoA GTP-Binding Protein / metabolism

Substances

Guanine Nucleotide Exchange Factors
PLEKHG6 protein, human
Protein Isoforms
rhoA GTP-Binding Protein